RARE DISEASE
Therapy related acute myeloid leukemia and myelodysplastic syndrome
Therapy related acute myeloid leukemia and myelodysplastic syndrome
Therapy related acute myeloid leukemia and myelodysplastic syndrome
Synonyms: Secondary AML, Secondary acute myeloid leukemia, Therapy-related AML and myelodysplastic syndrome
Synonyms: Secondary AML, Secondary acute myeloid leukemia, Therapy-related AML and myelodysplastic syndrome
Synonyms: Secondary AML, Secondary acute myeloid leukemia, Therapy-related AML and myelodysplastic syndrome
Drug discovery
0
drugs
With orphan designations
Overview
Therapy-related acute myeloid leukemia and myelodysplastic syndromes (t-AML/MDS) are aggressive clonal disorders arising after cytotoxic chemotherapy and/or radiotherapy. Characterized by high-risk genetic abnormalities and poor prognoses, they typically manifest 3–5 years post-treatment, with shorter latency after hematopoietic cell transplantation (HCT) [1][8]. Two distinct subtypes exist: alkylating agent/radiation-associated cases often show TP53 mutations and chromosome 5/7 abnormalities, while topoisomerase II inhibitor-linked cases frequently involve KMT2A rearrangements [1][8][9]. Median survival remains <1 year without allogeneic HCT [1][4].
Population
Primarily affects cancer survivors treated with chemoradiotherapy (e.g., Hodgkin/non-Hodgkin lymphoma, breast cancer) [1][2][9]
Risk elevated by alkylators, radiation, and HCT conditioning regimens [2][8]
10-20% of adult AML/MDS cases; incidence rising with expanded use of DNA-damaging therapies [5][8]
Therapies
Allogeneic HCT remains cornerstone for eligible patients, offering 30-43% long-term survival [1][4][8]
Hypomethylating agents (azacitidine/decitabine) as bridge to transplant or palliative option [6][9]
Supportive care with transfusions, growth factors, and infection prophylaxis for non-HCT candidates [3][9]
Categories: rare hematological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
3,254 drug discovery papers about Therapy related acute myeloid leukemia and myelodysplastic syndrome, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
3,254 drug discovery papers about Therapy related acute myeloid leukemia and myelodysplastic syndrome, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-17 | Real-world outcomes of venetoclax plus hypomethylating agents in unfit acute myeloid leukaemia: Results of the GIMEMA AML2320 trial.
Venetoclax (VEN) plus hypomethylating agents (HMAs) represents the standard of care for newly diagnosed acute myeloid leukaemia (AML) patients unfit for intensive chemotherapy, but prospective real-world observational data outside randomized clinical trials remain limited. The Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) AML2320 is a prospective, multicentre, observational study (NCT04589728) including 193 newly diagnosed unfit AML patients receiving VEN plus azacitidine or decitabine between November 2020 and December 2021. Primary end-point was overall survival (OS); secondary end-points included composite complete remission (cCR), disease-free survival and safety. Median age was 74 years with 42% of patients being ≥75 years. After completing cycle 4, cCR was achieved in 73% of the patients, with 54% responding before cycle 2. After a median follow-up of 23 months, median OS was 13.0 months. cCR achievement within cycle 4 correlated with longer OS (19.1 vs. 9.1 months, p = 0.001). Patients receiving 400 mg VEN without azoles had improved OS compared with those on reduced doses with azoles (18.2 vs. 11.4 months, p = 0.015). An anchored matching-adjusted indirect comparison with the phase III VIALE-A trial (NCT02993523) showed comparable median OS (14.8 months vs. 14.9 months; p = 0.6). The GIMEMA AML2320 trial confirmed the efficacy of VEN/HMAs in a prospective, real-world unfit population. Early remission was associated with improved outcomes.
2026-08-15 | Epigenetic Priming with Azacitidine Prior to Allogeneic Hematopoietic Stem Cell Transplantation for Myeloid Malignancies.
Relapse remains the leading cause of treatment failure following allogeneic hematopoietic stem cell transplantation (alloHCT) for high-risk myeloid malignancies. Epigenetic dysregulation contributes to leukemogenesis and therapeutic resistance. OBJECTIVE: : To investigate whether pre-transplant epigenetic priming with azacitidine enhances chemosensitivity and improves alloHCT outcomes. We conducted an open-label, prospective phase II study evaluating azacitidine incorporated into reduced-intensity conditioning in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing alloHCT from matched related or unrelated donors. The primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints included relapse incidence, non-relapse mortality (NRM), and pharmacodynamic evaluation of DNA methylation changes in bone marrow CD34+ cells. Thirty-nine patients were enrolled. Most patients had AML (85%), 62% with adverse-risk AML or high/very high-risk MDS, and 23% had TP53 mutations. Neutrophil and platelet engraftment occurred in 97% of patients at median of 13 and 16 days, respectively. One-year OS and PFS were 64% and 54%, respectively, with NRM of 15% and relapse incidence of 31%. Pharmacodynamic analyses demonstrated azacitidine-induced DNA hypomethylation in bone marrow CD34+ cells, which correlated with improved survival. Higher baseline methylation levels were also associated with superior survival. Azacitidine priming prior to alloHCT is feasible and demonstrates encouraging survival outcomes in high-risk myeloid malignancies. Epigenetic priming induces measurable biologic reduction of DNA methylation that is plausibly linked to improved relapse-free survival. These findings support further evaluation in randomized studies and suggest DNA methylation may serve as a predictive biomarker of response.
2026-08-08 | Prognostic factors for early mortality following allogeneic hematopoietic cell transplantation in hematologic malignancies.
The 100 days following allogeneic hematopoietic stem cell transplantation (allo-HCT) remains a critical period despite advancements in transplant-related care. Post-transplant cyclophosphamide (PTCy) has been implemented as an effective strategy for GVHD prevention across various donor types. This study aimed to evaluate causes of early mortality and prognostic factors for non-relapse mortality (NRM), disease-related mortality (DRM), and overall survival (OS). This was a single institution, retrospective study including adult patients who received their first allo-HCT from 2009 to 2023. Patient- and transplant- related variables were compared between patients who died and those who were alive at 100 days post-allo-HCT. A total of 536 patients were evaluated, including 285 men (53%). Median age at time of allo-HCT was 59 years (range 19-75), and most were White/Caucasian (n=232; 86%). The predominant diagnosis included acute myeloid leukemia (AML) (n=195, 36%), myelodysplastic syndrome (MDS) (n=95, 18%), and myelofibrosis (MF) (n=57, 11%). Eighty patients (15%) died within 100 days following allo-HCT, with NRM accounting for most early deaths (N=61; 76%). Primary causes of death were acute GVHD (n = 23), disease relapse/progression (n = 19), and infections (n = 18). On multivariate analysis, earlier transplant year was the only independent predictor of increased 100-day DRM (HR 1.15; p=0.049). Male gender (HR 1.78; p=0.035), non-acute leukemia diagnoses (HR 2.38; p=0.003), and non-PTCy prophylaxis (HR 2.2; p=0.032) were independently associated with higher 100-day NRM. PTCy-based GVHD prophylaxis was the only modifiable factor associated with lower early NRM, through reduced GVHD-related deaths without increased infection or DRM.
2026-08-06 | Defining a Therapeutic Window for Venetoclax in Post-Transplant Maintenance Therapy for High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndromes.
Patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) continue to face a substantial risk of relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT), which remains a leading cause of treatment failure. In our previous study, maintenance therapy with a combination of venetoclax and decitabine has shown potential in reducing relapse rates; however, its efficacy and safety, particularly in relation to drug concentration levels, are not yet fully elucidated. This study aimed to evaluate the influence of venetoclax blood concentrations on the efficacy and toxicity of venetoclax plus decitabine as maintenance therapy in high-risk AML/MDS patients after allo-HSCT. We retrospectively analyzed clinical data from 58 high-risk AML/MDS patients who received this maintenance regimen at our center between April 2018 and June 2023, with a focus on the association between venetoclax blood levels, treatment response, and adverse effects. The results demonstrated that the venetoclax-decitabine maintenance regimen was effective and generally well-tolerated, improving remission rates without significantly increasing intolerable toxicities or the risk of graft-versus-host disease (GVHD). Notably, substantial interindividual variability in venetoclax blood concentrations was observed. Patients with concentrations maintained within the range of 2605-4060 ng/mL achieved superior outcomes and higher safety profiles. In conclusion, this study provides key evidence for establishing a target concentration window for venetoclax, highlighting the importance of therapeutic drug monitoring in guiding post-transplant maintenance therapy for high-risk AML/MDS patients.
2026-07-23 | LY3410738, a Covalent Inhibitor of Mutant IDH1/2, is Effective in Acute Myeloid Leukemia Preclinical Models.
Acute myeloid leukemia (AML) is an aggressive blood disorder characterized by rapid growth of poorly differentiated myeloid cells. Gain-of-function mutations in isocitrate dehydrogenases (IDHs) are detected in ~20% of AML and ~80% of secondary gliomas. Mutant IDH1/2 isoenzymes acquire neomorphic activity to produce 2-hydroxyglutarate (2-HG) oncometabolite, resulting in hypermethylated DNA and histones, altered gene expression, and blocked differentiation of hematopoietic progenitors. Here, we presented preclinical development of LY3410738, an oral, dual IDH1/2 inhibitor with potential to penetrate the blood-brain barrier. LY3410738 covalently inhibited mutated-IDH1/2, reduced 2-HG levels at low nanomolar concentrations in human AML and glioma models, and demonstrated efficacy in AML patient-derived xenografts (PDXs) in vivo, inducing myeloid differentiation. LY3410738 retained in vitro activity in cancer models with acquired secondary IDH1/2 mutations conferring resistance to ivosidenib and enasidenib. LY3410738 synergized and was well tolerated with standard-of-care regimens such as cytarabine, azacitidine, venetoclax, or midostaurin in IDH1/2-mutated AML PDXs.
antibodies
2026-06-12 | Myeloid Malignancies Beyond the Cell: Targeting the Tumour Microenvironment with Next-Generation Immunotherapies.
Myeloid malignancies encompass a heterogeneous group of haematological disorders, primarily including myelodysplastic syndromes (MDSs) and myeloproliferative neoplasms (MPNs). MDS is characterised by defective myeloid cell maturation, while MPNs involve the pathological overproduction of myeloid lineage cells. In the absence of timely diagnosis and effective clinical intervention, both entities carry a substantial risk of progression to acute myeloid leukaemia (AML). Although allogeneic haematopoietic stem cell transplantation remains the only potentially curative therapy, its application is frequently constrained by patient-related factors such as advanced age and comorbid conditions. While currently, hypomethylating agent therapy (azacitidine and decitabine) is mainly used in high-risk MDS patients, and ruxolitinib is primarily used in symptomatic primary myelofibrosis (PMF-MPN), their clinical efficacy remains suboptimal. More recently, focus has turned toward the role of the tumour microenvironment (TME) in disease pathogenesis and whether therapeutically targeting the TME, either alone or in combination with conventional therapy, could present a new treatment option. Emerging evidence underscores the significant influence of TME components, particularly macrophages and T cells, in modulating immune responses and shaping the leukaemic niche to either facilitate or hinder malignant progression. In response, a new generation of immune checkpoint inhibitors are being developed to target the TME, including PD-1/CTLA-4 blockers, macrophage-directed agents including CD47 inhibitors, and T cell-targeting checkpoint inhibitors such as TIM-1 and LAG-3. This review will describe the functional role of key TME constituents in the progression of myeloid malignancies and explore the current landscape and future potential of advanced cellular and molecular immunotherapies in the treatment of these disorders.
2026-06-10 | Effector-to-target ratio as a translational bottleneck for CD33 T-cell engagers in acute myeloid leukemia: a quantitative reanalysis of AMG 330.
A common, often unstated paradigm in T-cell engager (TCE) translation assumes that target-antigen density and drug exposure are the main efficacy drivers, with effector context secondary. This paradigm is visible in dose-escalation strategies and in the use of high-E:T screens as principal preclinical assays. We tested whether an alternative, receptor-saturation framework better organizes the published AMG 330 record in acute myeloid leukemia (AML). Receptor-saturation arguments motivate two qualitative expectations: at sufficiently high CD33 densities, EC 50 should show little systematic dependence on additional antigen density, and response should become increasingly constrained by effector availability and functional state. We tested these expectations using two statistical reanalyses of published AMG 330 data-log-linear regression of EC 50 on CD33 density across 11 AML cell lines, and a comparative effect-size analysis of effector-to-target (E:T) ratio versus CD33 expression in 38 primary AML samples-integrated with clinical exposure-response findings and effector-augmenting rescue studies. Both expectations were supported. CD33 density did not significantly predict EC 50 across the 3.9-fold range tested ( p = 0.13 ; bootstrap 95% CI on slope includes zero). In primary samples, E:T ratio dominated sustained lysis by approximately an order of magnitude over CD33 expression (92.4 vs. 8.5 percentage points; CD33 effect p = 0.7 , not significant). Clinical exposure-response analyses identified baseline E:T ratio and T-cell PD-1 expression as response correlates. A similar target-effector dissociation has been reported in several other TCE programs. The AMG 330 record is more coherently organized by an effector-context framework than by the conventional target-density-and-exposure paradigm. These findings indicate that endogenous-effector assays, paired target-effector biomarkers, and rational effector-support strategies are likely to be clinically informative complements to conventional cell-line potency and dose-escalation approaches in future CD33 TCE development.
2026-05-20 | A PBD-dimer containing antibody drug conjugate targeting CCRL2 for high-risk MDS/AML including TP53-mutated disease.
Patients with myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) with high-risk features including TP53 mutations have poor outcomes due to lack of effective therapies. The atypical chemokine surface receptor C-C motif chemokine receptor-like 2 (CCRL2) is overexpressed in MDS and secondary AML (sAML) compared to healthy hematopoietic cells and we recently found that TP53-mutated MDS/AML and AML with erythroid features express the highest levels of this receptor across MDS/AML subtypes. To illustrate the therapeutic potential of CCRL2 as a therapeutic target, we developed an anti-CCRL2 antibody-drug conjugate (ADC) by conjugating an anti-CCRL2 antibody with the cytotoxic drug pyrrolobenzodiazepine (PBD), which causes DNA double-strand breaks leading to cancer cell death. The anti-CCRL2 ADC demonstrated strong CCRL2-selective cytotoxicity against cell lines derived from MDS/AML patients with TP53 mutations and erythroid features, surpassing the cytotoxic effects observed with gemtuzumab and PBD-conjugated anti-CD33 and anti-CD123 ADCs. It also induced apoptosis and suppressed the clonogenicity of primary MDS/AML bone marrow samples without affecting the survival, differentiation and clonogenicity of healthy hematopoietic stem and progenitor cells. This agent also suppressed the leukemic growth of TP53-mutated MDS/AML cell line xenografts, improving mice survival and decreasing the leukemic burden in patient-derived TP53-mutated MDS/AML xenografts. In conclusion, our study introduces CCRL2 as a potential new therapeutic target in high-risk MDS/AML including TP53-mutated subsets.
2026-03-20 | Diagnostic updates and research advances in AML-MR: Integrating molecular genetics and immune mechanisms.
Acute myeloid leukaemia, myelodysplasia-related (AML-MR) is a distinct subtype of acute myeloid leukemia defined in the 2022 WHO classification. It is characterized by specific molecular genetic abnormalities and immunological features. In recent years, with the continuous refinement of AML classification criteria and the incorporation of more precise molecular biomarkers into the diagnostic system, the accuracy of diagnosis and the precision of risk stratification have been significantly improved, laying the foundation for personalized treatment. Studies have shown that the development of AML-MR is closely associated with clonal hematopoietic abnormalities and dysregulation of the bone marrow immune microenvironment. This immunosuppressive state not only promotes leukemic progression but also affects therapeutic responses. In terms of treatment, emerging immunotherapies have shown promising advances in AML-MR, offering new directions for improving the prognosis of high-risk patients. This review systematically summarizes recent progress in the classification criteria, molecular genetic mechanisms, immune microenvironment characteristics, and targeted therapeutic strategies of AML-MR, aiming to provide insights for optimizing clinical management and guiding future research.
2026-02-05 | Enhancing CAR- and TCR-mediated targeting of cancer via an immune synapse-stabilizing receptor.
Heterogeneity in antigen expression on cancer cells limits clinical benefit of engineered T-cell therapies and underpins treatment resistance through antigen escape. Here, we present a strategy to improve recognition and lysis of tumors with suboptimal antigen expression through a separate engineered receptor that selectively boosts cytotoxic signaling and immune synapse formation. This synapse-stabilizing receptor (SSR) harbors a modified linker for activation of T cells (LAT) endodomain that amplifies CD3ζ signaling upon binding to a secondary tumor antigen resulting in an augmented Ca2+ flux, activation of MAPK and NF-kB signaling, maturation of immune synapse, and enhanced T-cell degranulation. Removing C-terminal amino acids 178-233 in the LAT endodomain (LAT177) was necessary to minimize SSR-mediated cytotoxicity. In models of acute myeloid leukemia, we show that a CD38-targeting SSR boosts cytolysis of antigen-low cancer cells via a C-type lectin-like molecule-1 (CLL1)-specific chimeric antigen receptor (CAR) and a survivin-specific T cell receptor (TCR). Unlike another CAR, SSR does not produce significant cytotoxicity against normal CD38+ tissues. Our study thus shows that SSR arming enhances targeting of antigenically heterogeneous cancers without compromising safety and selectivity of therapeutic T cells.
cell therapies
2026-07-15 | Simultaneous Leukocytapheresis and Continuous Renal Replacement Therapy for Acute Myeloid Leukemia: A Case Report.
Hyperleukocytosis in acute myeloid leukemia (AML) could cause life-threatening complications, including leukostasis and tumor lysis syndrome (TLS). While leukocytapheresis and continuous renal replacement therapy (CRRT) are typically performed independently to maintain hemodynamic stability and manage anticoagulation, their simultaneous application is rarely reported. We report a case of a deteriorating patient with secondary AML treated with simultaneous leukocytapheresis and CRRT. For the CRRT circuit, two separate hemodialysis catheters were placed in the femoral vein (access) and internal jugular vein (return). The leukocytapheresis circuit was then connected to the CRRT return line. The procedure was completed without immediate bleeding or thrombotic complications. Reductions in white blood cell counts, ammonia, and lactic acid levels were observed, along with improved oxygenation. Simultaneous leukocytapheresis and CRRT can be a safe and effective modality for the urgent management of hyperleukocytosis and TLS in critically ill patients.
2026-06-30 | T-cell replete haploidentical transplantation compared to mismatched unrelated allogeneic transplantation with post-transplantation cyclophosphamide in patients with secondary acute myeloid leukemia in first complete remission: A study from the ALWP/EBMT.
Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative option for secondary acute myeloid leukemia (sAML). Post-transplant cyclophosphamide has improved graft-versus-host disease (GVHD) prophylaxis, enabling the broader use of alternative donors. For patients lacking a human leukocyte antigen (HLA)-matched donor, haploidentical donor (Haplo) or 9/10 HLA mismatched unrelated donor (MMUD) HSCTs are widely used, yet their relative effectiveness in sAML is uncertain. We retrospectively compared outcomes after Haplo versus MMUD HSCT in adults with sAML in first complete remission transplanted between 2010 and 2022. Among 711 patients, 602 received Haplo and 109 MMUD grafts. Patient and transplant characteristics differed between cohorts, including donor age, conditioning intensity, graft source, and transplant year. Neutrophil recovery was faster after MMUD transplantation, while platelet recovery was comparable. Rates of acute and chronic GVHD, relapse incidence, non-relapse mortality, overall survival, leukemia-free survival, and GVHD-free/relapse-free survival were similar. Reduced intensity conditioning lowered acute GVHD risk, while peripheral blood grafts increased chronic GVHD. Lower Karnofsky score, older age and adverse-risk cytogenetics were adverse prognostic factors. Haplo and MMUD transplantation demonstrated comparable efficacy and safety with post-transplant cyclophosphamide, supporting both approaches as viable alternatives in the absence of an HLA-matched donor.
2026-06-25 | UCMSC-Exo for chemotherapy-induced myelosuppression in acute myeloid leukemia: a phase I clinical trial protocol.
Myelosuppression induced by chemotherapy represents a critical bottleneck for patients with hematological malignancies, leading to a series of severe complications responsible for chemotherapy dose reduction, interruptions, and even treatment-related death. There exists an urgent need for strategies to repair the bone marrow microenvironment and thus promote early recovery from myelosuppression. Umbilical cord-derived mesenchymal stem cell exosomes (UCMSC-Exo), as the key effector of stem cells, exhibit multi-target characteristics, making them a promising candidate for bone marrow structural reconstruction and functional remodeling. This study is a single-arm, open-label, dose-escalation, single-center, phase I clinical trial designed to evaluate the safety, tolerability, and preliminary efficacy of UCMSC-Exo in the treatment of chemotherapy-induced myelosuppression in patients with acute myeloid leukemia. Nine to eighteen eligible participants will be enrolled sequentially into three UCMSC-Exo dose-escalation groups to receive a single infusion, after which they will be followed up for 12 months. The primary endpoints focus on safety and tolerability. Secondary endpoints include parameters assessing myelosuppression recovery, the incidence of myelosuppression-related complications, and supportive care. The study protocol has been approved by the Ethics Committee of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology.Clinical trial registration: NCT06245746.
2026-06-22 | Non-myeloablative versus reduced intensity conditioning for allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia patients aged ≥65: a study from the ALWP of EBMT.
The optimal conditioning intensity for allogeneic hematopoietic stem cell transplantation (allo-HCT) in elderly acute myeloid leukemia (AML) remains elusive. We retrospectively analyzed 2900 AML patients aged ≥65 in complete remission who underwent allo-HCT from 2004 to 2021. Conditioning was classified as reduced-intensity conditioning (RIC: fludarabine with busulfan, melphalan, or treosulfan) or non-myeloablative (NMA: fludarabine with total body irradiation). Primary endpoints were overall survival (OS) and leukemia-free survival (LFS); secondary endpoints included non-relapse mortality (NRM), acute and chronic graft-versus-host disease (GVHD), and GVHD/relapse-free survival (GRFS). With follow-up censored to account for differences between arms, OS, LFS, and NRM at 2 years were similar between RIC and NMA on multivariable analysis. Peripheral blood stem cells (PBSC) were independently associated with superior OS (HR 0.67, p = 0.002) and LFS (HR 0.71, p = 0.008) versus bone marrow grafts. GRFS was equivalent between conditioning intensities, although RIC was associated with higher acute GVHD and NMA with higher extensive chronic GVHD. In exploratory analysis, OS and LFS were similar across RIC regimens (Flu/Bu2 as reference: Flu/Mel OS HR 0.91, p = 0.53; Flu/Treo OS HR 0.89, p = 0.42). In older AML patients in remission, RIC and NMA yield comparable survival and NRM; PBSC grafts may be associated with superior outcomes although this warrants validation.
2026-05-13 | CRISPR-Cas9 CD33-deleted allogeneic hematopoietic cell transplantation with gemtuzumab ozogamicin maintenance in AML: a phase 1/2 trial.
Patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are likely to relapse despite allogenic hematopoietic cell transplantation (HCT). Post-HCT preventative maintenance can be limited by toxicity toward the normal donor cells. Tremtelectogene empogeditemcel (trem-cel) is a CRISPR-Cas9 gene-edited allogeneic HCT product lacking CD33, designed to shield the donor graft from cytotoxicity of subsequent CD33-targeted therapies such as gemtuzumab ozogamicin (GO). In this multicenter, phase 1/2a, open-label study, adult patients with AML/MDS with high relapse risk received trem-cel after myeloablative conditioning followed by GO maintenance (0.5-2.0 mg m-2 day 1 per 28-day cycles). Patients receiving trem-cel were assessed for the primary safety endpoint of neutrophil engraftment by day 28 and secondary endpoints including time to neutrophil engraftment, incidence of graft-versus-host disease and graft failure, transplant-related mortality, percentage of CD33-negative myeloid cells and survival. Patients receiving trem-cel and GO were assessed for the additional secondary endpoints of safety of maintenance GO with trem-cel and pharmacokinetics of GO after trem-cel transplant. All 30 patients receiving trem-cel achieved the primary safety endpoint of neutrophil engraftment by day 28 with a median engraftment time of 10 days (95% confidence interval: 9-10). Nineteen patients received GO maintenance in phase 1 dose escalation (n = 15) and in phase 2 dose expansion (n = 4). The trial was stopped early, and this is the final report on the trial including the completed phase 1 portion. GO treatment was safely tolerated up to the recommended phase 2 dose of 2 mg m-2, and no prolonged high-grade cytopenias were observed. The most common adverse events were cytopenias and infections. Three cases of transplant-related mortality were observed due to renal failure, sepsis and sinusoidal obstruction syndrome, respectively. In summary, trem-cel demonstrated safe, rapid, robust engraftment, and GO maintenance was administered without prolonged hematologic toxicity. ClinicalTrials.gov identifier: NCT04849910 .
proteins
2026-08-12 | Treatment Modalities and the Impact of Granulocyte Colony-Stimulating Factor in AML Patients Treated With Venetoclax and Azacitidine: A DATAML Registry Study.
Azacitidine-venetoclax (AZA-VEN) has become a standard treatment in older or chemotherapy-ineligible AML patients. While the registration trial showed a median overall survival (OS) of 14.7 months, most real-world studies have not reproduced this result. We analyzed treatment patterns, adverse events, responses and outcomes in 199 patients treated with AZA-VEN in the DATAML registry. The median age was 75.6 years, 48.7% had secondary AML (11% post-MPN); 11.7% had another cancer, and 9% had received AZA for prior myelodysplastic syndrome. Cytogenetic risk was intermediate (55.8%) or adverse (43.7%). The most frequent gene mutations were ASXL1 (33%), TET2 (27%), TP53 (26%), RUNX1 (24%) and SRSF2 (24%). The first cycle was performed on an outpatient basis in 39.4% of patients. The median number of cycles was 4 and 37% received > 6 cycles. Beyond cycle 6, reductions in treatment dose or duration were attributed to VEN in 55% of patients and to AZA for 43%. The complete remission (CR) plus CR with incomplete hematologic recovery (CRi) rate was 58.5%, and day-30 death rate was 3%. Median OS was 8.9 months. mPRS and refined-ELN2024 classifications were significantly associated with response and OS. In CR/CRi patients, G-CSF use was significantly and independently associated with improved OS (median, 10.1 months without versus 20.3 with G-CSF; P = .001). In an external cohort, G-CSF was also associated with a trend towards improved OS. In real-world clinical practice, patients with more severe characteristics are typically selected for AZA-VEN, which could explain suboptimal outcomes. G-CSF should be prospectively explored in AZA-VEN treated patients.
2025-09-21 | Pathogenic mechanisms and targeted therapies for anemia in myelodysplastic syndromes.
Myelodysplastic Syndromes (MDS) are malignant neoplasms of the myeloid lineage originating from hematopoietic stem cells (HSCs), characterized by ineffective hematopoiesis, blood cell dysplasia, and a high risk of transformation to acute leukemia. Anemia affects up to 90 % of MDS patients, significantly increasing symptom burden, impacting quality of life, accelerating disease progression, and is associated with increased morbidity and mortality. The limited therapeutic landscape for addressing anemia in MDS presents a significant challenge in clinical management. This review explores the mechanisms of anemia in MDS（including low-risk MDS and high-risk MDS）, covering disturbances in hematopoiesis, telomere dynamics, inflammation, immune dysregulation, alterations in iron metabolism, and the role of the bone marrow microenvironment. We examine how these factors contribute to the complex pathophysiology of MDS-related anemia and discuss their implications for treatment strategies. Furthermore, we highlight recent advances in understanding the molecular basis of MDS, which have paved the way for novel therapeutic approaches. These include targeted therapies addressing specific genetic mutations, immunomodulatory agents, and innovative approaches to stimulate effective erythropoiesis. We also review emerging treatments such as Luspatercept, along with other novel agents targeting specific pathways, and ongoing clinical trials exploring combination therapies and personalized treatment strategies.
2025-05-28 | Overall survival (OS) and duration of response for transfusion independence (TI) in erythropoiesis stimulating agent (ESA)–naive patients (pts) with very low-, low-, or intermediate-risk myelodysplastic syndromes (MDS) treated with luspatercept (LUSPA) vs epoetin alfa (EA) in the COMMANDS trial.
6512 Background: In the phase 3 COMMANDS trial (NCT03682536), LUSPA was superior in improving red blood cell (RBC)-TI ≥12 wks with concurrent hemoglobin increase ≥1.5 g/dL in Wks 1 to 24 vs EA and had durable clinical benefit in pts with ESA-naive transfusion-dependent (TD) lower-risk MDS (LR-MDS; Della Porta MG, et al. Lancet Haematol . 2024; Garcia-Manero G, et al. ASH. 2024). Here, we report updated results including OS and duration of response. Methods: Eligible pts (≥18 yrs; ESA-naive; RBC TD; very low/low/intermediate-risk MDS) were randomized 1:1 (stratified by baseline [BL] RBC transfusion burden [TB], serum erythropoietin [EPO] level, and ring sideroblast [RS] status) to receive LUSPA (1.0-1.75 mg/kg) SC Q3W or EA (450-1050 IU/kg; max dose 80,000 IU) SC QW for ≥24 wks. Secondary endpoints included OS, duration of RBC-TI ≥12 wks, and safety. Results: As of Nov 4, 2024, median follow up (FU) was 29.0 and 27.1 mos for the LUSPA (n=182) and EA (n=181) groups, respectively. Median OS for LUSPA was not reached (NR) and was 46.7 mos for EA (HR, 0.86; 95% CI, 0.60-1.24); 3-yr OS rates were 63.8% and 62.2%, respectively, and 5-yr OS rates were 54.0% and 41.8%. In subgroups, similar OS trends were observed (Table). Overall, RBC-TI ≥12 wks (Wk 1 to end of treatment [EOT]) was reached by 76.4% (139/182) of pts in the LUSPA group and 55.8% (101/181) in the EA group. Median cumulative duration (95% CI) of RBC-TI ≥12 wks (sum of all durations of RBC-TI ≥12 wks episodes from Wk 1 to EOT) was 187.3 (119.6-NE) wks for LUSPA vs 94.9 (73.1-179.0) wks for EA (HR, 0.51; 95% CI, 0.34-0.77). Median duration (95% CI) of longest RBC-TI ≥12 wks period (from Wk 1 to EOT) was 126.6 (81.0-184.4) vs 86.7 (55.9-111.1) wks (HR, 0.64; 95% CI, 0.44-0.93). At cutoff, 24.7% of LUSPA pts and 11.2% of EA pts were on treatment; 84.6% and 82.7%, respectively, had ≥1 dose escalation. With longer FU, no new safety concerns emerged. Deaths occurred in both groups on- (10.4% vs 9.5%) and post-treatment (20.9% vs 26.3%). Progression to acute myeloid leukemia was comparable between groups (3.8% vs 4.4%). Conclusions: LUSPA led to improvements in response rate and duration, with a positive OS trend requiring further evaluation through more extended follow up. LUSPA signifies a new standard of care for anemia in first-line LR-MDS. Clinical trial information: NCT03682536 . Median OS, mos LUSPA EA HR (95% CI) Overall (ITT) (n=182)NR (n=181)46.7 0.86 (0.60-1.24) Stratification subgroup BL TB <4 U (n=118)NR (n=111)46.7 0.87(0.55-1.38) BL TB ≥4 U (n=64)NR (n=70)48.2 0.74(0.42-1.31) RS+ (n=133)NR (n=130)48.2 0.77(0.50-1.19) RS− (n=49)NR (n=50)46.2 0.93(0.50-1.75) BL EPO ≤200 U/L (n=145)NR (n=144)51.4 0.84(0.55-1.27) BL EPO >200 U/L (n=37)NR (n=37)35.4 0.81(0.40-1.64) ITT, intention-to-treat; U, units.
2024-07-12 | The Impact of Prophylactic Post-Chemotherapy G-CSF on the Relapse Rates in Patients with Acute Myeloid Leukemia: A Meta-Analysis.
This meta-analysis evaluated the impact of prophylactic post-chemotherapy granulocyte colony-stimulating factor (G-CSF) in patients with acute myeloid leukemia (AML). Overall, the relapse rate, overall survival, event-free survival, and mortality rate were similar in G-CSF (+) compared to G-CSF (-) patients. However, the relative risk (RR) of relapse was higher in children and in secondary AML patients who were treated with G-CSF compared to the G-CSF (-) group [RR, 95% confidence interval: 1.26, 1.04-1.52, and 1.12 (1.02-1.24)]. Treatment with post-chemotherapy G-CSF should be prescribed with caution in pediatric patients with AML and secondary AML as possibly increasing the relapse risk.
2024-02-27 | Treatment with the apoptosis inhibitor Asunercept reduces clone sizes in patients with lower risk Myelodysplastic Neoplasms
Abstract In low-risk Myelodysplastic Neoplasms (MDS), increased activity of apoptosis-promoting factors such as tumor necrosis factor (TNFα) and pro-apoptotic Fas ligand (CD95L) have been described as possible pathomechanisms leading to impaired erythropoiesis. Asunercept (APG101) is a novel therapeutic fusion protein blocking CD95, which has previously shown partial efficacy in reducing transfusion requirement in a clinical phase I trial for low-risk MDS patients (NCT01736436; 2012-11-26). In the current study we aimed to evaluate the effect of Asunercept therapy on the clonal bone marrow composition to identify potential biomarkers to predict response. Bone marrow samples of n = 12 low-risk MDS patients from the above referenced clinical trial were analyzed by serial deep whole exome sequencing in a total of n = 58 time points. We could distinguish a mean of 3.5 molecularly defined subclones per patient (range 2–6). We observed a molecular response defined as reductions of dominant clone sizes by a variant allele frequency (VAF) decrease of at least 10% (mean 20%, range: 10.5–39.2%) in dependency of Asunercept treatment in 9 of 12 (75%) patients. Most of this decline in clonal populations was observed after completion of 12 weeks treatment. Particularly early and pronounced reductions of clone sizes were found in subclones driven by mutations in genes involved in regulation of methylation ( n = 1 DNMT3A , n = 1 IDH2 , n = 1 TET2 ). Our results suggest that APG101 could be efficacious in reducing clone sizes of mutated hematopoietic cells in the bone marrow of Myelodysplastic Neoplasms, which warrants further investigation.
other
2026-04-01 | mRNA vaccines in cancer immunotherapy: current progress and perspectives in solid tumors and hematologic malignancies.
The unprecedented success of mRNA vaccines during the COVID-19 pandemic has accelerated the development of nucleic acid-based therapeutics, particularly in oncology. Decades of foundational research on mRNA design, delivery, and immunogenicity have laid the groundwork for the application of mRNA vaccines in cancer treatment. Herein, we summarize the key principles of synthetic mRNA engineering, including the optimization of structural elements, nucleoside modification, and codon usage to improve stability, enhance translation efficiency, and modulate immune responses. We highlight diverse antigen strategies, including tumor-associated antigens; neoantigens; and novel sources, such as cryptic antigens, aberrant splicing variants, and transposable element-derived antigens. We discuss delivery platforms, particularly lipid nanoparticles (LNPs) and dendritic cell-based systems, in the context of improving mRNA biodistribution and immune activation. We further examine how mRNA vaccines stimulate antitumor responses by encoding antigens, modulating the tumor microenvironment, and supporting adoptive T cell therapies. We review preclinical and clinical advances in combining mRNA vaccine with immune checkpoint inhibitors for the treatment of solid tumors (e.g., melanoma, pancreatic cancer, and glioblastoma) and hematologic malignancies (e.g., acute myeloid leukemia, myelodysplastic syndrome, and multiple myeloma). Finally, we explore emerging innovations, such as targeted LNP platforms for in vivo chimeric antigen receptor T/T cell receptor T engineering and artificial intelligence-assisted vaccine design, underscoring the transformative potential of mRNA technology in cancer immunotherapy.
2025-10-18 | Acute Leukemias of Ambiguous Lineage With RUNX1 Mutations Show Similar Prognosis Compared to Acute Myeloid Leukemia With RUNX1 Mutations: A Study From the Bone Marrow Pathology Group.
The World Health Organization (WHO) 5th Edition and International Consensus Classification (ICC) have continued to delineate more genetically defined acute leukemias. Both recognize genetic aberrations associated with myelodysplastic syndromes/neoplasms (MDS) as defining MDS-related AML (AML-MR). Mutations in RUNX1 are included in this category in the ICC, but not WHO. The current classifications are unclear on how acute leukemias with ambiguous lineage (ALAL), including those of mixed lineage (MPAL) and those without a defined lineage (AUL), should be categorized in the presence of such mutations. Our multi-institutional study aims to determine the significance of RUNX1 mutation in ALAL compared to de novo AML. Newly diagnosed MPAL, AUL, and AML with RUNX1 mutations were collected. ALAL with MDS-related cytogenetics, BCR::ABL1, KMT2A rearrangements, or ZNF384 or BCL11b abnormalities were excluded. We analyzed 17 cases of ALAL and 71 cases of AML that met inclusion criteria. ALAL-RUNX1 and AML-RUNX1 showed overlapping mutational landscapes with frequent comutations in MDS-associated genes. No ALAL-RUNX1 or AML-RUNX1 cases showed concomitant TP53 mutation. ALAL-RUNX1 had more bone marrow blasts and more karyotypic abnormalities; however, neither impacted survival, nor did RUNX1 variant allele frequency (VAF). Survival analysis revealed similarly poor outcomes between them. AML-directed therapies and allogeneic hematopoietic stem cell transplant trended toward improved survival in ALAL-RUNX1; however, it did not reach significance. Our results suggest ALAL-RUNX1 is associated with younger age, higher blasts, and more karyotypic abnormalities, but has similar clinical and genetic features and outcomes to AML-RUNX1. Our findings suggest, like other MR mutations, RUNX1-mutated ALALs should be included within AML-MR.
2025-04-21 | Abstract 6500: Application of human inducible pluripotent stem cells (hiPSCs) with CRISPR/Cas9-mediated deletion of CUX1 as a model for high-risk myeloid neoplasms
Abstract Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with cytogenetic abnormalities of chromosome 7 have dismal survival outcomes. Monosomy 7 or deletion of 7q (-7/del7q) are adverse-risk cytogenetic features found in up to 12% of MDS/AML patients and are further enriched in therapy-related MDS/AML. Despite significant scientific effort, no targeted therapy is available for patients with -7/del7q MDS/AML. Several genes are associated with -7/del7q leukemogenesis. Cut-like homeobox 1 (CUX1) is a gene encoding a context-dependent transcription factor required for several molecular pathways, including epigenetic signaling. CUX1 is deleted in -7/del7q MDS/AML and somatically mutated in 2-4% of MDS/AML. CUX1 mutations and CUX1 deletions are associated with a poor prognosis, and are known to co-occur with adverse risk TP53 mutations and a complex cytogenetic background. Thus, there is a need for novel human models of MDS/AML to isolate the effect of CUX1 alterations. To address the need for high-fidelity models of MDS/AML with high-risk genetic changes, we transfected human inducible pluripotent stem cells (hiPSCs) with CUX1 targeting gRNA and CRISPR/Cas9 ribonucleotide-protein (RNP) complexes to generate isogenic hiPSC lines bearing CUX1+/- and CUX1-/- genotypes alongside parent hiPSCs and sham transfection lines with a CUX1+/+ background. These derivative cell lines underwent rigorous validation by karyotypic G-banding analysis, sequencing, immunoblotting, trilineage germ layer differentiation, and analysis of hiPSC transcriptional and immunophenotypic markers. We hypothesized that the loss of one or both alleles of CUX1 would result in transcriptional changes similar to CUX1 mutated and -7/del7q MDS/AML. This model can be further leveraged to identify potential treatment targets. We obtained bulk RNA sequencing of undifferentiated hiPSCs and hiPSC-derived hematopoietic stem and progenitor cells (i-HSPCs) of each genotype (CUX1+/+, CUX1+/-, and CUX1-/-). We identified several differentially expressed genes and novel long non-coding RNAs in hiPSCs with Cas9-mediated CUX1 deletions, including downregulation of distinct subsets of genes in CUX1-/- and CUX1+/- hiPSCs. Bulk RNA sequencing of CUX1-/- and CUX1+/- i-HSPCs identified an association between reduced expression of thioredoxin-interacting protein (TXNIP), a known regulator of autophagy. This study supports the use of hiPSC-based CRISPR/Cas9 gene editing as a novel platform to identify gene-specific alterations in genotypically and cytogenetically complex myeloid neoplasms. Citation Format: Joseph Michael Cannova, Kaina A. Millan, Yuqing Xue, Aubrianna S. Ramsland, Zara Khosravi, Adesewa Ogunsusi, Matthew Jotte, Megan McNerney, Michael Drazer. Application of human inducible pluripotent stem cells (hiPSCs) with CRISPR/Cas9-mediated deletion of CUX1 as a model for high-risk myeloid neoplasms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6500.
2024-10-29 | AML-VAC-XS15-01: protocol of a first-in-human clinical trial to evaluate the safety, tolerability and preliminary efficacy of a multi-peptide vaccine based on leukemia stem cell antigens in acute myeloid leukemia patients.
Acute myeloid leukemia (AML) has a dismal prognosis, mostly due to minimal residual disease-driven relapse, making an elimination of persisting therapy-resistant leukemia progenitor/stem cells (LPCs) the main goal for novel therapies. Peptide-based immunotherapy offers a low-side-effect approach aiming to induce T cell responses directed against human leukocyte antigen (HLA) presented tumor antigens on malignant cells by therapeutic vaccination. Mass spectrometry-based analysis of the naturally presented immunopeptidome of primary enriched LPC and AML samples enabled the selection of antigens exclusively expressed on LPC/AML cells, which showed de novo induction and spontaneous memory T cell responses in AML patients, and whose presentation and memory T cell recognition was associated with improved disease outcome. Based on these data the therapeutic vaccine AML-VAC-XS15 was designed, comprising two mutated HLA class I-restricted peptides from the common AML-specific mutation in NPM1 and seven HLA class II-restricted peptides (six non-mutated high-frequent AML/LPC-associated antigens and one mutated peptide from the AML-specific mutation R140Q in IDH2), adjuvanted with the toll like receptor 1/2 ligand XS15 and emulsified in Montanide ISA 51 VG. A phase I open label clinical trial investigating AML-VAC-XS15 was designed, recruiting AML patients in complete cytological remission (CR) or CR with incomplete blood count recovery. Patients are vaccinated twice with a six-week interval, with an optional booster vaccination four months after 2nd vaccination, and are then followed up for two years. The trial's primary objectives are the assessment of the vaccine's immunogenicity, safety and toxicity, secondary objectives include characterization of vaccine-induced T cell responses and assessment of preliminary clinical efficacy. The AML-VAC-XS15-01 study was approved by the Ethics Committee of the Bavarian State medical association and the Paul-Ehrlich Institut (P01392). Clinical trial results will be published in peer-reviewed journals.
2024-07-11 | Germ line ERG haploinsufficiency defines a new syndrome with cytopenia and hematological malignancy predisposition.
The genomics era has facilitated the discovery of new genes that predispose individuals to bone marrow failure (BMF) and hematological malignancy (HM). We report the discovery of ETS-related gene (ERG), a novel, autosomal dominant BMF/HM predisposition gene. ERG is a highly constrained transcription factor that is critical for definitive hematopoiesis, stem cell function, and platelet maintenance. ERG colocalizes with other transcription factors, including RUNX family transcription factor 1 (RUNX1) and GATA binding protein 2 (GATA2), on promoters or enhancers of genes that orchestrate hematopoiesis. We identified a rare heterozygous ERG missense variant in 3 individuals with thrombocytopenia from 1 family and 14 additional ERG variants in unrelated individuals with BMF/HM, including 2 de novo cases and 3 truncating variants. Phenotypes associated with pathogenic germ line ERG variants included cytopenias (thrombocytopenia, neutropenia, and pancytopenia) and HMs (acute myeloid leukemia, myelodysplastic syndrome, and acute lymphoblastic leukemia) with onset before 40 years. Twenty ERG variants (19 missense and 1 truncating), including 3 missense population variants, were functionally characterized. Thirteen potentially pathogenic erythroblast transformation specific (ETS) domain missense variants displayed loss-of-function (LOF) characteristics, thereby disrupting transcriptional transactivation, DNA binding, and/or nuclear localization. Selected variants overexpressed in mouse fetal liver cells failed to drive myeloid differentiation and cytokine-independent growth in culture and to promote acute erythroleukemia when transplanted into mice, concordant with these being LOF variants. Four individuals displayed somatic genetic rescue by copy neutral loss of heterozygosity. Identification of predisposing germ line ERG variants has clinical implications for patient and family diagnoses, counseling, surveillance, and treatment strategies, including selection of bone marrow donors and cell or gene therapy.
small molecules
2026-08-17 | Real-world outcomes of venetoclax plus hypomethylating agents in unfit acute myeloid leukaemia: Results of the GIMEMA AML2320 trial.
Venetoclax (VEN) plus hypomethylating agents (HMAs) represents the standard of care for newly diagnosed acute myeloid leukaemia (AML) patients unfit for intensive chemotherapy, but prospective real-world observational data outside randomized clinical trials remain limited. The Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) AML2320 is a prospective, multicentre, observational study (NCT04589728) including 193 newly diagnosed unfit AML patients receiving VEN plus azacitidine or decitabine between November 2020 and December 2021. Primary end-point was overall survival (OS); secondary end-points included composite complete remission (cCR), disease-free survival and safety. Median age was 74 years with 42% of patients being ≥75 years. After completing cycle 4, cCR was achieved in 73% of the patients, with 54% responding before cycle 2. After a median follow-up of 23 months, median OS was 13.0 months. cCR achievement within cycle 4 correlated with longer OS (19.1 vs. 9.1 months, p = 0.001). Patients receiving 400 mg VEN without azoles had improved OS compared with those on reduced doses with azoles (18.2 vs. 11.4 months, p = 0.015). An anchored matching-adjusted indirect comparison with the phase III VIALE-A trial (NCT02993523) showed comparable median OS (14.8 months vs. 14.9 months; p = 0.6). The GIMEMA AML2320 trial confirmed the efficacy of VEN/HMAs in a prospective, real-world unfit population. Early remission was associated with improved outcomes.
2026-08-15 | Epigenetic Priming with Azacitidine Prior to Allogeneic Hematopoietic Stem Cell Transplantation for Myeloid Malignancies.
Relapse remains the leading cause of treatment failure following allogeneic hematopoietic stem cell transplantation (alloHCT) for high-risk myeloid malignancies. Epigenetic dysregulation contributes to leukemogenesis and therapeutic resistance. OBJECTIVE: : To investigate whether pre-transplant epigenetic priming with azacitidine enhances chemosensitivity and improves alloHCT outcomes. We conducted an open-label, prospective phase II study evaluating azacitidine incorporated into reduced-intensity conditioning in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing alloHCT from matched related or unrelated donors. The primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints included relapse incidence, non-relapse mortality (NRM), and pharmacodynamic evaluation of DNA methylation changes in bone marrow CD34+ cells. Thirty-nine patients were enrolled. Most patients had AML (85%), 62% with adverse-risk AML or high/very high-risk MDS, and 23% had TP53 mutations. Neutrophil and platelet engraftment occurred in 97% of patients at median of 13 and 16 days, respectively. One-year OS and PFS were 64% and 54%, respectively, with NRM of 15% and relapse incidence of 31%. Pharmacodynamic analyses demonstrated azacitidine-induced DNA hypomethylation in bone marrow CD34+ cells, which correlated with improved survival. Higher baseline methylation levels were also associated with superior survival. Azacitidine priming prior to alloHCT is feasible and demonstrates encouraging survival outcomes in high-risk myeloid malignancies. Epigenetic priming induces measurable biologic reduction of DNA methylation that is plausibly linked to improved relapse-free survival. These findings support further evaluation in randomized studies and suggest DNA methylation may serve as a predictive biomarker of response.
2026-08-08 | Prognostic factors for early mortality following allogeneic hematopoietic cell transplantation in hematologic malignancies.
The 100 days following allogeneic hematopoietic stem cell transplantation (allo-HCT) remains a critical period despite advancements in transplant-related care. Post-transplant cyclophosphamide (PTCy) has been implemented as an effective strategy for GVHD prevention across various donor types. This study aimed to evaluate causes of early mortality and prognostic factors for non-relapse mortality (NRM), disease-related mortality (DRM), and overall survival (OS). This was a single institution, retrospective study including adult patients who received their first allo-HCT from 2009 to 2023. Patient- and transplant- related variables were compared between patients who died and those who were alive at 100 days post-allo-HCT. A total of 536 patients were evaluated, including 285 men (53%). Median age at time of allo-HCT was 59 years (range 19-75), and most were White/Caucasian (n=232; 86%). The predominant diagnosis included acute myeloid leukemia (AML) (n=195, 36%), myelodysplastic syndrome (MDS) (n=95, 18%), and myelofibrosis (MF) (n=57, 11%). Eighty patients (15%) died within 100 days following allo-HCT, with NRM accounting for most early deaths (N=61; 76%). Primary causes of death were acute GVHD (n = 23), disease relapse/progression (n = 19), and infections (n = 18). On multivariate analysis, earlier transplant year was the only independent predictor of increased 100-day DRM (HR 1.15; p=0.049). Male gender (HR 1.78; p=0.035), non-acute leukemia diagnoses (HR 2.38; p=0.003), and non-PTCy prophylaxis (HR 2.2; p=0.032) were independently associated with higher 100-day NRM. PTCy-based GVHD prophylaxis was the only modifiable factor associated with lower early NRM, through reduced GVHD-related deaths without increased infection or DRM.
2026-08-06 | Defining a Therapeutic Window for Venetoclax in Post-Transplant Maintenance Therapy for High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndromes.
Patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) continue to face a substantial risk of relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT), which remains a leading cause of treatment failure. In our previous study, maintenance therapy with a combination of venetoclax and decitabine has shown potential in reducing relapse rates; however, its efficacy and safety, particularly in relation to drug concentration levels, are not yet fully elucidated. This study aimed to evaluate the influence of venetoclax blood concentrations on the efficacy and toxicity of venetoclax plus decitabine as maintenance therapy in high-risk AML/MDS patients after allo-HSCT. We retrospectively analyzed clinical data from 58 high-risk AML/MDS patients who received this maintenance regimen at our center between April 2018 and June 2023, with a focus on the association between venetoclax blood levels, treatment response, and adverse effects. The results demonstrated that the venetoclax-decitabine maintenance regimen was effective and generally well-tolerated, improving remission rates without significantly increasing intolerable toxicities or the risk of graft-versus-host disease (GVHD). Notably, substantial interindividual variability in venetoclax blood concentrations was observed. Patients with concentrations maintained within the range of 2605-4060 ng/mL achieved superior outcomes and higher safety profiles. In conclusion, this study provides key evidence for establishing a target concentration window for venetoclax, highlighting the importance of therapeutic drug monitoring in guiding post-transplant maintenance therapy for high-risk AML/MDS patients.
2026-07-23 | LY3410738, a Covalent Inhibitor of Mutant IDH1/2, is Effective in Acute Myeloid Leukemia Preclinical Models.
Acute myeloid leukemia (AML) is an aggressive blood disorder characterized by rapid growth of poorly differentiated myeloid cells. Gain-of-function mutations in isocitrate dehydrogenases (IDHs) are detected in ~20% of AML and ~80% of secondary gliomas. Mutant IDH1/2 isoenzymes acquire neomorphic activity to produce 2-hydroxyglutarate (2-HG) oncometabolite, resulting in hypermethylated DNA and histones, altered gene expression, and blocked differentiation of hematopoietic progenitors. Here, we presented preclinical development of LY3410738, an oral, dual IDH1/2 inhibitor with potential to penetrate the blood-brain barrier. LY3410738 covalently inhibited mutated-IDH1/2, reduced 2-HG levels at low nanomolar concentrations in human AML and glioma models, and demonstrated efficacy in AML patient-derived xenografts (PDXs) in vivo, inducing myeloid differentiation. LY3410738 retained in vitro activity in cancer models with acquired secondary IDH1/2 mutations conferring resistance to ivosidenib and enasidenib. LY3410738 synergized and was well tolerated with standard-of-care regimens such as cytarabine, azacitidine, venetoclax, or midostaurin in IDH1/2-mutated AML PDXs.
antibodies
2026-06-12 | Myeloid Malignancies Beyond the Cell: Targeting the Tumour Microenvironment with Next-Generation Immunotherapies.
Myeloid malignancies encompass a heterogeneous group of haematological disorders, primarily including myelodysplastic syndromes (MDSs) and myeloproliferative neoplasms (MPNs). MDS is characterised by defective myeloid cell maturation, while MPNs involve the pathological overproduction of myeloid lineage cells. In the absence of timely diagnosis and effective clinical intervention, both entities carry a substantial risk of progression to acute myeloid leukaemia (AML). Although allogeneic haematopoietic stem cell transplantation remains the only potentially curative therapy, its application is frequently constrained by patient-related factors such as advanced age and comorbid conditions. While currently, hypomethylating agent therapy (azacitidine and decitabine) is mainly used in high-risk MDS patients, and ruxolitinib is primarily used in symptomatic primary myelofibrosis (PMF-MPN), their clinical efficacy remains suboptimal. More recently, focus has turned toward the role of the tumour microenvironment (TME) in disease pathogenesis and whether therapeutically targeting the TME, either alone or in combination with conventional therapy, could present a new treatment option. Emerging evidence underscores the significant influence of TME components, particularly macrophages and T cells, in modulating immune responses and shaping the leukaemic niche to either facilitate or hinder malignant progression. In response, a new generation of immune checkpoint inhibitors are being developed to target the TME, including PD-1/CTLA-4 blockers, macrophage-directed agents including CD47 inhibitors, and T cell-targeting checkpoint inhibitors such as TIM-1 and LAG-3. This review will describe the functional role of key TME constituents in the progression of myeloid malignancies and explore the current landscape and future potential of advanced cellular and molecular immunotherapies in the treatment of these disorders.
2026-06-10 | Effector-to-target ratio as a translational bottleneck for CD33 T-cell engagers in acute myeloid leukemia: a quantitative reanalysis of AMG 330.
A common, often unstated paradigm in T-cell engager (TCE) translation assumes that target-antigen density and drug exposure are the main efficacy drivers, with effector context secondary. This paradigm is visible in dose-escalation strategies and in the use of high-E:T screens as principal preclinical assays. We tested whether an alternative, receptor-saturation framework better organizes the published AMG 330 record in acute myeloid leukemia (AML). Receptor-saturation arguments motivate two qualitative expectations: at sufficiently high CD33 densities, EC 50 should show little systematic dependence on additional antigen density, and response should become increasingly constrained by effector availability and functional state. We tested these expectations using two statistical reanalyses of published AMG 330 data-log-linear regression of EC 50 on CD33 density across 11 AML cell lines, and a comparative effect-size analysis of effector-to-target (E:T) ratio versus CD33 expression in 38 primary AML samples-integrated with clinical exposure-response findings and effector-augmenting rescue studies. Both expectations were supported. CD33 density did not significantly predict EC 50 across the 3.9-fold range tested ( p = 0.13 ; bootstrap 95% CI on slope includes zero). In primary samples, E:T ratio dominated sustained lysis by approximately an order of magnitude over CD33 expression (92.4 vs. 8.5 percentage points; CD33 effect p = 0.7 , not significant). Clinical exposure-response analyses identified baseline E:T ratio and T-cell PD-1 expression as response correlates. A similar target-effector dissociation has been reported in several other TCE programs. The AMG 330 record is more coherently organized by an effector-context framework than by the conventional target-density-and-exposure paradigm. These findings indicate that endogenous-effector assays, paired target-effector biomarkers, and rational effector-support strategies are likely to be clinically informative complements to conventional cell-line potency and dose-escalation approaches in future CD33 TCE development.
2026-05-20 | A PBD-dimer containing antibody drug conjugate targeting CCRL2 for high-risk MDS/AML including TP53-mutated disease.
Patients with myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) with high-risk features including TP53 mutations have poor outcomes due to lack of effective therapies. The atypical chemokine surface receptor C-C motif chemokine receptor-like 2 (CCRL2) is overexpressed in MDS and secondary AML (sAML) compared to healthy hematopoietic cells and we recently found that TP53-mutated MDS/AML and AML with erythroid features express the highest levels of this receptor across MDS/AML subtypes. To illustrate the therapeutic potential of CCRL2 as a therapeutic target, we developed an anti-CCRL2 antibody-drug conjugate (ADC) by conjugating an anti-CCRL2 antibody with the cytotoxic drug pyrrolobenzodiazepine (PBD), which causes DNA double-strand breaks leading to cancer cell death. The anti-CCRL2 ADC demonstrated strong CCRL2-selective cytotoxicity against cell lines derived from MDS/AML patients with TP53 mutations and erythroid features, surpassing the cytotoxic effects observed with gemtuzumab and PBD-conjugated anti-CD33 and anti-CD123 ADCs. It also induced apoptosis and suppressed the clonogenicity of primary MDS/AML bone marrow samples without affecting the survival, differentiation and clonogenicity of healthy hematopoietic stem and progenitor cells. This agent also suppressed the leukemic growth of TP53-mutated MDS/AML cell line xenografts, improving mice survival and decreasing the leukemic burden in patient-derived TP53-mutated MDS/AML xenografts. In conclusion, our study introduces CCRL2 as a potential new therapeutic target in high-risk MDS/AML including TP53-mutated subsets.
2026-03-20 | Diagnostic updates and research advances in AML-MR: Integrating molecular genetics and immune mechanisms.
Acute myeloid leukaemia, myelodysplasia-related (AML-MR) is a distinct subtype of acute myeloid leukemia defined in the 2022 WHO classification. It is characterized by specific molecular genetic abnormalities and immunological features. In recent years, with the continuous refinement of AML classification criteria and the incorporation of more precise molecular biomarkers into the diagnostic system, the accuracy of diagnosis and the precision of risk stratification have been significantly improved, laying the foundation for personalized treatment. Studies have shown that the development of AML-MR is closely associated with clonal hematopoietic abnormalities and dysregulation of the bone marrow immune microenvironment. This immunosuppressive state not only promotes leukemic progression but also affects therapeutic responses. In terms of treatment, emerging immunotherapies have shown promising advances in AML-MR, offering new directions for improving the prognosis of high-risk patients. This review systematically summarizes recent progress in the classification criteria, molecular genetic mechanisms, immune microenvironment characteristics, and targeted therapeutic strategies of AML-MR, aiming to provide insights for optimizing clinical management and guiding future research.
2026-02-05 | Enhancing CAR- and TCR-mediated targeting of cancer via an immune synapse-stabilizing receptor.
Heterogeneity in antigen expression on cancer cells limits clinical benefit of engineered T-cell therapies and underpins treatment resistance through antigen escape. Here, we present a strategy to improve recognition and lysis of tumors with suboptimal antigen expression through a separate engineered receptor that selectively boosts cytotoxic signaling and immune synapse formation. This synapse-stabilizing receptor (SSR) harbors a modified linker for activation of T cells (LAT) endodomain that amplifies CD3ζ signaling upon binding to a secondary tumor antigen resulting in an augmented Ca2+ flux, activation of MAPK and NF-kB signaling, maturation of immune synapse, and enhanced T-cell degranulation. Removing C-terminal amino acids 178-233 in the LAT endodomain (LAT177) was necessary to minimize SSR-mediated cytotoxicity. In models of acute myeloid leukemia, we show that a CD38-targeting SSR boosts cytolysis of antigen-low cancer cells via a C-type lectin-like molecule-1 (CLL1)-specific chimeric antigen receptor (CAR) and a survivin-specific T cell receptor (TCR). Unlike another CAR, SSR does not produce significant cytotoxicity against normal CD38+ tissues. Our study thus shows that SSR arming enhances targeting of antigenically heterogeneous cancers without compromising safety and selectivity of therapeutic T cells.
cell therapies
2026-07-15 | Simultaneous Leukocytapheresis and Continuous Renal Replacement Therapy for Acute Myeloid Leukemia: A Case Report.
Hyperleukocytosis in acute myeloid leukemia (AML) could cause life-threatening complications, including leukostasis and tumor lysis syndrome (TLS). While leukocytapheresis and continuous renal replacement therapy (CRRT) are typically performed independently to maintain hemodynamic stability and manage anticoagulation, their simultaneous application is rarely reported. We report a case of a deteriorating patient with secondary AML treated with simultaneous leukocytapheresis and CRRT. For the CRRT circuit, two separate hemodialysis catheters were placed in the femoral vein (access) and internal jugular vein (return). The leukocytapheresis circuit was then connected to the CRRT return line. The procedure was completed without immediate bleeding or thrombotic complications. Reductions in white blood cell counts, ammonia, and lactic acid levels were observed, along with improved oxygenation. Simultaneous leukocytapheresis and CRRT can be a safe and effective modality for the urgent management of hyperleukocytosis and TLS in critically ill patients.
2026-06-30 | T-cell replete haploidentical transplantation compared to mismatched unrelated allogeneic transplantation with post-transplantation cyclophosphamide in patients with secondary acute myeloid leukemia in first complete remission: A study from the ALWP/EBMT.
Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative option for secondary acute myeloid leukemia (sAML). Post-transplant cyclophosphamide has improved graft-versus-host disease (GVHD) prophylaxis, enabling the broader use of alternative donors. For patients lacking a human leukocyte antigen (HLA)-matched donor, haploidentical donor (Haplo) or 9/10 HLA mismatched unrelated donor (MMUD) HSCTs are widely used, yet their relative effectiveness in sAML is uncertain. We retrospectively compared outcomes after Haplo versus MMUD HSCT in adults with sAML in first complete remission transplanted between 2010 and 2022. Among 711 patients, 602 received Haplo and 109 MMUD grafts. Patient and transplant characteristics differed between cohorts, including donor age, conditioning intensity, graft source, and transplant year. Neutrophil recovery was faster after MMUD transplantation, while platelet recovery was comparable. Rates of acute and chronic GVHD, relapse incidence, non-relapse mortality, overall survival, leukemia-free survival, and GVHD-free/relapse-free survival were similar. Reduced intensity conditioning lowered acute GVHD risk, while peripheral blood grafts increased chronic GVHD. Lower Karnofsky score, older age and adverse-risk cytogenetics were adverse prognostic factors. Haplo and MMUD transplantation demonstrated comparable efficacy and safety with post-transplant cyclophosphamide, supporting both approaches as viable alternatives in the absence of an HLA-matched donor.
2026-06-25 | UCMSC-Exo for chemotherapy-induced myelosuppression in acute myeloid leukemia: a phase I clinical trial protocol.
Myelosuppression induced by chemotherapy represents a critical bottleneck for patients with hematological malignancies, leading to a series of severe complications responsible for chemotherapy dose reduction, interruptions, and even treatment-related death. There exists an urgent need for strategies to repair the bone marrow microenvironment and thus promote early recovery from myelosuppression. Umbilical cord-derived mesenchymal stem cell exosomes (UCMSC-Exo), as the key effector of stem cells, exhibit multi-target characteristics, making them a promising candidate for bone marrow structural reconstruction and functional remodeling. This study is a single-arm, open-label, dose-escalation, single-center, phase I clinical trial designed to evaluate the safety, tolerability, and preliminary efficacy of UCMSC-Exo in the treatment of chemotherapy-induced myelosuppression in patients with acute myeloid leukemia. Nine to eighteen eligible participants will be enrolled sequentially into three UCMSC-Exo dose-escalation groups to receive a single infusion, after which they will be followed up for 12 months. The primary endpoints focus on safety and tolerability. Secondary endpoints include parameters assessing myelosuppression recovery, the incidence of myelosuppression-related complications, and supportive care. The study protocol has been approved by the Ethics Committee of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology.Clinical trial registration: NCT06245746.
2026-06-22 | Non-myeloablative versus reduced intensity conditioning for allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia patients aged ≥65: a study from the ALWP of EBMT.
The optimal conditioning intensity for allogeneic hematopoietic stem cell transplantation (allo-HCT) in elderly acute myeloid leukemia (AML) remains elusive. We retrospectively analyzed 2900 AML patients aged ≥65 in complete remission who underwent allo-HCT from 2004 to 2021. Conditioning was classified as reduced-intensity conditioning (RIC: fludarabine with busulfan, melphalan, or treosulfan) or non-myeloablative (NMA: fludarabine with total body irradiation). Primary endpoints were overall survival (OS) and leukemia-free survival (LFS); secondary endpoints included non-relapse mortality (NRM), acute and chronic graft-versus-host disease (GVHD), and GVHD/relapse-free survival (GRFS). With follow-up censored to account for differences between arms, OS, LFS, and NRM at 2 years were similar between RIC and NMA on multivariable analysis. Peripheral blood stem cells (PBSC) were independently associated with superior OS (HR 0.67, p = 0.002) and LFS (HR 0.71, p = 0.008) versus bone marrow grafts. GRFS was equivalent between conditioning intensities, although RIC was associated with higher acute GVHD and NMA with higher extensive chronic GVHD. In exploratory analysis, OS and LFS were similar across RIC regimens (Flu/Bu2 as reference: Flu/Mel OS HR 0.91, p = 0.53; Flu/Treo OS HR 0.89, p = 0.42). In older AML patients in remission, RIC and NMA yield comparable survival and NRM; PBSC grafts may be associated with superior outcomes although this warrants validation.
2026-05-13 | CRISPR-Cas9 CD33-deleted allogeneic hematopoietic cell transplantation with gemtuzumab ozogamicin maintenance in AML: a phase 1/2 trial.
Patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are likely to relapse despite allogenic hematopoietic cell transplantation (HCT). Post-HCT preventative maintenance can be limited by toxicity toward the normal donor cells. Tremtelectogene empogeditemcel (trem-cel) is a CRISPR-Cas9 gene-edited allogeneic HCT product lacking CD33, designed to shield the donor graft from cytotoxicity of subsequent CD33-targeted therapies such as gemtuzumab ozogamicin (GO). In this multicenter, phase 1/2a, open-label study, adult patients with AML/MDS with high relapse risk received trem-cel after myeloablative conditioning followed by GO maintenance (0.5-2.0 mg m-2 day 1 per 28-day cycles). Patients receiving trem-cel were assessed for the primary safety endpoint of neutrophil engraftment by day 28 and secondary endpoints including time to neutrophil engraftment, incidence of graft-versus-host disease and graft failure, transplant-related mortality, percentage of CD33-negative myeloid cells and survival. Patients receiving trem-cel and GO were assessed for the additional secondary endpoints of safety of maintenance GO with trem-cel and pharmacokinetics of GO after trem-cel transplant. All 30 patients receiving trem-cel achieved the primary safety endpoint of neutrophil engraftment by day 28 with a median engraftment time of 10 days (95% confidence interval: 9-10). Nineteen patients received GO maintenance in phase 1 dose escalation (n = 15) and in phase 2 dose expansion (n = 4). The trial was stopped early, and this is the final report on the trial including the completed phase 1 portion. GO treatment was safely tolerated up to the recommended phase 2 dose of 2 mg m-2, and no prolonged high-grade cytopenias were observed. The most common adverse events were cytopenias and infections. Three cases of transplant-related mortality were observed due to renal failure, sepsis and sinusoidal obstruction syndrome, respectively. In summary, trem-cel demonstrated safe, rapid, robust engraftment, and GO maintenance was administered without prolonged hematologic toxicity. ClinicalTrials.gov identifier: NCT04849910 .
proteins
2026-08-12 | Treatment Modalities and the Impact of Granulocyte Colony-Stimulating Factor in AML Patients Treated With Venetoclax and Azacitidine: A DATAML Registry Study.
Azacitidine-venetoclax (AZA-VEN) has become a standard treatment in older or chemotherapy-ineligible AML patients. While the registration trial showed a median overall survival (OS) of 14.7 months, most real-world studies have not reproduced this result. We analyzed treatment patterns, adverse events, responses and outcomes in 199 patients treated with AZA-VEN in the DATAML registry. The median age was 75.6 years, 48.7% had secondary AML (11% post-MPN); 11.7% had another cancer, and 9% had received AZA for prior myelodysplastic syndrome. Cytogenetic risk was intermediate (55.8%) or adverse (43.7%). The most frequent gene mutations were ASXL1 (33%), TET2 (27%), TP53 (26%), RUNX1 (24%) and SRSF2 (24%). The first cycle was performed on an outpatient basis in 39.4% of patients. The median number of cycles was 4 and 37% received > 6 cycles. Beyond cycle 6, reductions in treatment dose or duration were attributed to VEN in 55% of patients and to AZA for 43%. The complete remission (CR) plus CR with incomplete hematologic recovery (CRi) rate was 58.5%, and day-30 death rate was 3%. Median OS was 8.9 months. mPRS and refined-ELN2024 classifications were significantly associated with response and OS. In CR/CRi patients, G-CSF use was significantly and independently associated with improved OS (median, 10.1 months without versus 20.3 with G-CSF; P = .001). In an external cohort, G-CSF was also associated with a trend towards improved OS. In real-world clinical practice, patients with more severe characteristics are typically selected for AZA-VEN, which could explain suboptimal outcomes. G-CSF should be prospectively explored in AZA-VEN treated patients.
2025-09-21 | Pathogenic mechanisms and targeted therapies for anemia in myelodysplastic syndromes.
Myelodysplastic Syndromes (MDS) are malignant neoplasms of the myeloid lineage originating from hematopoietic stem cells (HSCs), characterized by ineffective hematopoiesis, blood cell dysplasia, and a high risk of transformation to acute leukemia. Anemia affects up to 90 % of MDS patients, significantly increasing symptom burden, impacting quality of life, accelerating disease progression, and is associated with increased morbidity and mortality. The limited therapeutic landscape for addressing anemia in MDS presents a significant challenge in clinical management. This review explores the mechanisms of anemia in MDS（including low-risk MDS and high-risk MDS）, covering disturbances in hematopoiesis, telomere dynamics, inflammation, immune dysregulation, alterations in iron metabolism, and the role of the bone marrow microenvironment. We examine how these factors contribute to the complex pathophysiology of MDS-related anemia and discuss their implications for treatment strategies. Furthermore, we highlight recent advances in understanding the molecular basis of MDS, which have paved the way for novel therapeutic approaches. These include targeted therapies addressing specific genetic mutations, immunomodulatory agents, and innovative approaches to stimulate effective erythropoiesis. We also review emerging treatments such as Luspatercept, along with other novel agents targeting specific pathways, and ongoing clinical trials exploring combination therapies and personalized treatment strategies.
2025-05-28 | Overall survival (OS) and duration of response for transfusion independence (TI) in erythropoiesis stimulating agent (ESA)–naive patients (pts) with very low-, low-, or intermediate-risk myelodysplastic syndromes (MDS) treated with luspatercept (LUSPA) vs epoetin alfa (EA) in the COMMANDS trial.
6512 Background: In the phase 3 COMMANDS trial (NCT03682536), LUSPA was superior in improving red blood cell (RBC)-TI ≥12 wks with concurrent hemoglobin increase ≥1.5 g/dL in Wks 1 to 24 vs EA and had durable clinical benefit in pts with ESA-naive transfusion-dependent (TD) lower-risk MDS (LR-MDS; Della Porta MG, et al. Lancet Haematol . 2024; Garcia-Manero G, et al. ASH. 2024). Here, we report updated results including OS and duration of response. Methods: Eligible pts (≥18 yrs; ESA-naive; RBC TD; very low/low/intermediate-risk MDS) were randomized 1:1 (stratified by baseline [BL] RBC transfusion burden [TB], serum erythropoietin [EPO] level, and ring sideroblast [RS] status) to receive LUSPA (1.0-1.75 mg/kg) SC Q3W or EA (450-1050 IU/kg; max dose 80,000 IU) SC QW for ≥24 wks. Secondary endpoints included OS, duration of RBC-TI ≥12 wks, and safety. Results: As of Nov 4, 2024, median follow up (FU) was 29.0 and 27.1 mos for the LUSPA (n=182) and EA (n=181) groups, respectively. Median OS for LUSPA was not reached (NR) and was 46.7 mos for EA (HR, 0.86; 95% CI, 0.60-1.24); 3-yr OS rates were 63.8% and 62.2%, respectively, and 5-yr OS rates were 54.0% and 41.8%. In subgroups, similar OS trends were observed (Table). Overall, RBC-TI ≥12 wks (Wk 1 to end of treatment [EOT]) was reached by 76.4% (139/182) of pts in the LUSPA group and 55.8% (101/181) in the EA group. Median cumulative duration (95% CI) of RBC-TI ≥12 wks (sum of all durations of RBC-TI ≥12 wks episodes from Wk 1 to EOT) was 187.3 (119.6-NE) wks for LUSPA vs 94.9 (73.1-179.0) wks for EA (HR, 0.51; 95% CI, 0.34-0.77). Median duration (95% CI) of longest RBC-TI ≥12 wks period (from Wk 1 to EOT) was 126.6 (81.0-184.4) vs 86.7 (55.9-111.1) wks (HR, 0.64; 95% CI, 0.44-0.93). At cutoff, 24.7% of LUSPA pts and 11.2% of EA pts were on treatment; 84.6% and 82.7%, respectively, had ≥1 dose escalation. With longer FU, no new safety concerns emerged. Deaths occurred in both groups on- (10.4% vs 9.5%) and post-treatment (20.9% vs 26.3%). Progression to acute myeloid leukemia was comparable between groups (3.8% vs 4.4%). Conclusions: LUSPA led to improvements in response rate and duration, with a positive OS trend requiring further evaluation through more extended follow up. LUSPA signifies a new standard of care for anemia in first-line LR-MDS. Clinical trial information: NCT03682536 . Median OS, mos LUSPA EA HR (95% CI) Overall (ITT) (n=182)NR (n=181)46.7 0.86 (0.60-1.24) Stratification subgroup BL TB <4 U (n=118)NR (n=111)46.7 0.87(0.55-1.38) BL TB ≥4 U (n=64)NR (n=70)48.2 0.74(0.42-1.31) RS+ (n=133)NR (n=130)48.2 0.77(0.50-1.19) RS− (n=49)NR (n=50)46.2 0.93(0.50-1.75) BL EPO ≤200 U/L (n=145)NR (n=144)51.4 0.84(0.55-1.27) BL EPO >200 U/L (n=37)NR (n=37)35.4 0.81(0.40-1.64) ITT, intention-to-treat; U, units.
2024-07-12 | The Impact of Prophylactic Post-Chemotherapy G-CSF on the Relapse Rates in Patients with Acute Myeloid Leukemia: A Meta-Analysis.
This meta-analysis evaluated the impact of prophylactic post-chemotherapy granulocyte colony-stimulating factor (G-CSF) in patients with acute myeloid leukemia (AML). Overall, the relapse rate, overall survival, event-free survival, and mortality rate were similar in G-CSF (+) compared to G-CSF (-) patients. However, the relative risk (RR) of relapse was higher in children and in secondary AML patients who were treated with G-CSF compared to the G-CSF (-) group [RR, 95% confidence interval: 1.26, 1.04-1.52, and 1.12 (1.02-1.24)]. Treatment with post-chemotherapy G-CSF should be prescribed with caution in pediatric patients with AML and secondary AML as possibly increasing the relapse risk.
2024-02-27 | Treatment with the apoptosis inhibitor Asunercept reduces clone sizes in patients with lower risk Myelodysplastic Neoplasms
Abstract In low-risk Myelodysplastic Neoplasms (MDS), increased activity of apoptosis-promoting factors such as tumor necrosis factor (TNFα) and pro-apoptotic Fas ligand (CD95L) have been described as possible pathomechanisms leading to impaired erythropoiesis. Asunercept (APG101) is a novel therapeutic fusion protein blocking CD95, which has previously shown partial efficacy in reducing transfusion requirement in a clinical phase I trial for low-risk MDS patients (NCT01736436; 2012-11-26). In the current study we aimed to evaluate the effect of Asunercept therapy on the clonal bone marrow composition to identify potential biomarkers to predict response. Bone marrow samples of n = 12 low-risk MDS patients from the above referenced clinical trial were analyzed by serial deep whole exome sequencing in a total of n = 58 time points. We could distinguish a mean of 3.5 molecularly defined subclones per patient (range 2–6). We observed a molecular response defined as reductions of dominant clone sizes by a variant allele frequency (VAF) decrease of at least 10% (mean 20%, range: 10.5–39.2%) in dependency of Asunercept treatment in 9 of 12 (75%) patients. Most of this decline in clonal populations was observed after completion of 12 weeks treatment. Particularly early and pronounced reductions of clone sizes were found in subclones driven by mutations in genes involved in regulation of methylation ( n = 1 DNMT3A , n = 1 IDH2 , n = 1 TET2 ). Our results suggest that APG101 could be efficacious in reducing clone sizes of mutated hematopoietic cells in the bone marrow of Myelodysplastic Neoplasms, which warrants further investigation.
other
2026-04-01 | mRNA vaccines in cancer immunotherapy: current progress and perspectives in solid tumors and hematologic malignancies.
The unprecedented success of mRNA vaccines during the COVID-19 pandemic has accelerated the development of nucleic acid-based therapeutics, particularly in oncology. Decades of foundational research on mRNA design, delivery, and immunogenicity have laid the groundwork for the application of mRNA vaccines in cancer treatment. Herein, we summarize the key principles of synthetic mRNA engineering, including the optimization of structural elements, nucleoside modification, and codon usage to improve stability, enhance translation efficiency, and modulate immune responses. We highlight diverse antigen strategies, including tumor-associated antigens; neoantigens; and novel sources, such as cryptic antigens, aberrant splicing variants, and transposable element-derived antigens. We discuss delivery platforms, particularly lipid nanoparticles (LNPs) and dendritic cell-based systems, in the context of improving mRNA biodistribution and immune activation. We further examine how mRNA vaccines stimulate antitumor responses by encoding antigens, modulating the tumor microenvironment, and supporting adoptive T cell therapies. We review preclinical and clinical advances in combining mRNA vaccine with immune checkpoint inhibitors for the treatment of solid tumors (e.g., melanoma, pancreatic cancer, and glioblastoma) and hematologic malignancies (e.g., acute myeloid leukemia, myelodysplastic syndrome, and multiple myeloma). Finally, we explore emerging innovations, such as targeted LNP platforms for in vivo chimeric antigen receptor T/T cell receptor T engineering and artificial intelligence-assisted vaccine design, underscoring the transformative potential of mRNA technology in cancer immunotherapy.
2025-10-18 | Acute Leukemias of Ambiguous Lineage With RUNX1 Mutations Show Similar Prognosis Compared to Acute Myeloid Leukemia With RUNX1 Mutations: A Study From the Bone Marrow Pathology Group.
The World Health Organization (WHO) 5th Edition and International Consensus Classification (ICC) have continued to delineate more genetically defined acute leukemias. Both recognize genetic aberrations associated with myelodysplastic syndromes/neoplasms (MDS) as defining MDS-related AML (AML-MR). Mutations in RUNX1 are included in this category in the ICC, but not WHO. The current classifications are unclear on how acute leukemias with ambiguous lineage (ALAL), including those of mixed lineage (MPAL) and those without a defined lineage (AUL), should be categorized in the presence of such mutations. Our multi-institutional study aims to determine the significance of RUNX1 mutation in ALAL compared to de novo AML. Newly diagnosed MPAL, AUL, and AML with RUNX1 mutations were collected. ALAL with MDS-related cytogenetics, BCR::ABL1, KMT2A rearrangements, or ZNF384 or BCL11b abnormalities were excluded. We analyzed 17 cases of ALAL and 71 cases of AML that met inclusion criteria. ALAL-RUNX1 and AML-RUNX1 showed overlapping mutational landscapes with frequent comutations in MDS-associated genes. No ALAL-RUNX1 or AML-RUNX1 cases showed concomitant TP53 mutation. ALAL-RUNX1 had more bone marrow blasts and more karyotypic abnormalities; however, neither impacted survival, nor did RUNX1 variant allele frequency (VAF). Survival analysis revealed similarly poor outcomes between them. AML-directed therapies and allogeneic hematopoietic stem cell transplant trended toward improved survival in ALAL-RUNX1; however, it did not reach significance. Our results suggest ALAL-RUNX1 is associated with younger age, higher blasts, and more karyotypic abnormalities, but has similar clinical and genetic features and outcomes to AML-RUNX1. Our findings suggest, like other MR mutations, RUNX1-mutated ALALs should be included within AML-MR.
2025-04-21 | Abstract 6500: Application of human inducible pluripotent stem cells (hiPSCs) with CRISPR/Cas9-mediated deletion of CUX1 as a model for high-risk myeloid neoplasms
Abstract Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with cytogenetic abnormalities of chromosome 7 have dismal survival outcomes. Monosomy 7 or deletion of 7q (-7/del7q) are adverse-risk cytogenetic features found in up to 12% of MDS/AML patients and are further enriched in therapy-related MDS/AML. Despite significant scientific effort, no targeted therapy is available for patients with -7/del7q MDS/AML. Several genes are associated with -7/del7q leukemogenesis. Cut-like homeobox 1 (CUX1) is a gene encoding a context-dependent transcription factor required for several molecular pathways, including epigenetic signaling. CUX1 is deleted in -7/del7q MDS/AML and somatically mutated in 2-4% of MDS/AML. CUX1 mutations and CUX1 deletions are associated with a poor prognosis, and are known to co-occur with adverse risk TP53 mutations and a complex cytogenetic background. Thus, there is a need for novel human models of MDS/AML to isolate the effect of CUX1 alterations. To address the need for high-fidelity models of MDS/AML with high-risk genetic changes, we transfected human inducible pluripotent stem cells (hiPSCs) with CUX1 targeting gRNA and CRISPR/Cas9 ribonucleotide-protein (RNP) complexes to generate isogenic hiPSC lines bearing CUX1+/- and CUX1-/- genotypes alongside parent hiPSCs and sham transfection lines with a CUX1+/+ background. These derivative cell lines underwent rigorous validation by karyotypic G-banding analysis, sequencing, immunoblotting, trilineage germ layer differentiation, and analysis of hiPSC transcriptional and immunophenotypic markers. We hypothesized that the loss of one or both alleles of CUX1 would result in transcriptional changes similar to CUX1 mutated and -7/del7q MDS/AML. This model can be further leveraged to identify potential treatment targets. We obtained bulk RNA sequencing of undifferentiated hiPSCs and hiPSC-derived hematopoietic stem and progenitor cells (i-HSPCs) of each genotype (CUX1+/+, CUX1+/-, and CUX1-/-). We identified several differentially expressed genes and novel long non-coding RNAs in hiPSCs with Cas9-mediated CUX1 deletions, including downregulation of distinct subsets of genes in CUX1-/- and CUX1+/- hiPSCs. Bulk RNA sequencing of CUX1-/- and CUX1+/- i-HSPCs identified an association between reduced expression of thioredoxin-interacting protein (TXNIP), a known regulator of autophagy. This study supports the use of hiPSC-based CRISPR/Cas9 gene editing as a novel platform to identify gene-specific alterations in genotypically and cytogenetically complex myeloid neoplasms. Citation Format: Joseph Michael Cannova, Kaina A. Millan, Yuqing Xue, Aubrianna S. Ramsland, Zara Khosravi, Adesewa Ogunsusi, Matthew Jotte, Megan McNerney, Michael Drazer. Application of human inducible pluripotent stem cells (hiPSCs) with CRISPR/Cas9-mediated deletion of CUX1 as a model for high-risk myeloid neoplasms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6500.
2024-10-29 | AML-VAC-XS15-01: protocol of a first-in-human clinical trial to evaluate the safety, tolerability and preliminary efficacy of a multi-peptide vaccine based on leukemia stem cell antigens in acute myeloid leukemia patients.
Acute myeloid leukemia (AML) has a dismal prognosis, mostly due to minimal residual disease-driven relapse, making an elimination of persisting therapy-resistant leukemia progenitor/stem cells (LPCs) the main goal for novel therapies. Peptide-based immunotherapy offers a low-side-effect approach aiming to induce T cell responses directed against human leukocyte antigen (HLA) presented tumor antigens on malignant cells by therapeutic vaccination. Mass spectrometry-based analysis of the naturally presented immunopeptidome of primary enriched LPC and AML samples enabled the selection of antigens exclusively expressed on LPC/AML cells, which showed de novo induction and spontaneous memory T cell responses in AML patients, and whose presentation and memory T cell recognition was associated with improved disease outcome. Based on these data the therapeutic vaccine AML-VAC-XS15 was designed, comprising two mutated HLA class I-restricted peptides from the common AML-specific mutation in NPM1 and seven HLA class II-restricted peptides (six non-mutated high-frequent AML/LPC-associated antigens and one mutated peptide from the AML-specific mutation R140Q in IDH2), adjuvanted with the toll like receptor 1/2 ligand XS15 and emulsified in Montanide ISA 51 VG. A phase I open label clinical trial investigating AML-VAC-XS15 was designed, recruiting AML patients in complete cytological remission (CR) or CR with incomplete blood count recovery. Patients are vaccinated twice with a six-week interval, with an optional booster vaccination four months after 2nd vaccination, and are then followed up for two years. The trial's primary objectives are the assessment of the vaccine's immunogenicity, safety and toxicity, secondary objectives include characterization of vaccine-induced T cell responses and assessment of preliminary clinical efficacy. The AML-VAC-XS15-01 study was approved by the Ethics Committee of the Bavarian State medical association and the Paul-Ehrlich Institut (P01392). Clinical trial results will be published in peer-reviewed journals.
2024-07-11 | Germ line ERG haploinsufficiency defines a new syndrome with cytopenia and hematological malignancy predisposition.
The genomics era has facilitated the discovery of new genes that predispose individuals to bone marrow failure (BMF) and hematological malignancy (HM). We report the discovery of ETS-related gene (ERG), a novel, autosomal dominant BMF/HM predisposition gene. ERG is a highly constrained transcription factor that is critical for definitive hematopoiesis, stem cell function, and platelet maintenance. ERG colocalizes with other transcription factors, including RUNX family transcription factor 1 (RUNX1) and GATA binding protein 2 (GATA2), on promoters or enhancers of genes that orchestrate hematopoiesis. We identified a rare heterozygous ERG missense variant in 3 individuals with thrombocytopenia from 1 family and 14 additional ERG variants in unrelated individuals with BMF/HM, including 2 de novo cases and 3 truncating variants. Phenotypes associated with pathogenic germ line ERG variants included cytopenias (thrombocytopenia, neutropenia, and pancytopenia) and HMs (acute myeloid leukemia, myelodysplastic syndrome, and acute lymphoblastic leukemia) with onset before 40 years. Twenty ERG variants (19 missense and 1 truncating), including 3 missense population variants, were functionally characterized. Thirteen potentially pathogenic erythroblast transformation specific (ETS) domain missense variants displayed loss-of-function (LOF) characteristics, thereby disrupting transcriptional transactivation, DNA binding, and/or nuclear localization. Selected variants overexpressed in mouse fetal liver cells failed to drive myeloid differentiation and cytokine-independent growth in culture and to promote acute erythroleukemia when transplanted into mice, concordant with these being LOF variants. Four individuals displayed somatic genetic rescue by copy neutral loss of heterozygosity. Identification of predisposing germ line ERG variants has clinical implications for patient and family diagnoses, counseling, surveillance, and treatment strategies, including selection of bone marrow donors and cell or gene therapy.
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